The present invention relates to a pharmaceutical formulation for the prophylaxis or preliminary treatment of a poisoning caused by organophosphorus cholinesterase inhibitors.
The present invention is to provide pharmaceutical formulations releasing suitable active substances in a controlled manner for the prophylactic treatment of poisonings caused by cholinesterase inhibitors. Examples of organophosphorus cholinesterase inhibitors include esters of phosphoric acid derivatives, e.g., nitrostigmine (=diethyl-(4-nitrophenyl)-thiophosphate, better known under the names Parathion or E 605), but they also include tabun, as well as the phosphonic acid derivatives sarin, soman and VX.
Among other things cholinesterase-inhibiting phosphoric esters are used as insecticides in agriculture. Since they also have a toxic effect on human beings, the staff working in agriculture is subject to a basic hazard to life and limb; this is true all the more since these organic phosphoric esters can also be absorbed via the skin. As compared to insecticides, the compounds tabun, sarin, soman and VX which belong to the group of the so-called nerve warfare agents are distinguished by a particularly high toxicity. All of these compounds are more or less strong inhibitors of the acetylcholinesterase, an enzyme which physiologically blocks the effect of the transmitter acetylcholine released at certain nerve endings. Most of the symptoms of poisoning caused by cholinesterase inhibitors are produced by an inundation with endogenic acetylcholine.
The basic drug therapy of such a poisoning consists in the administration of the parasympatholytic atropine, blocking the exceeding muscarinic acetylcholine effects (e.g., increase of secretion in the respiratory system, bronchospasm, inhibition of the central nervous respiratory drive). There is no suitable antagonist available to normalize the exceeding nicotinic acetylcholine actions (e.g., inhibition of the impulse transmission at the synapses of motorial nerves to the respiratory musculature and to other skeletal muscles up to a complete peripheral motor paralysis). The peripherally caused myoparesis can only be compensated by oximes, e.g., pralidoxime (PAM) or obidoxime (Toxogonin.RTM.) whose mechanism of action consists in a reactivation of the inhibited acetylcholinesterase.
Some of the phosphoric cholinesterase inhibitors are distinguished by the fact that they split off alkyl residues after accumulation to the acetylcholinesterase, thus stabilizing the bond ("aging"). The aged esterase inhibitor complex cannot be reactivated by oximes. In case of poisonings caused by the nerve warfare agent soman, aging already occurs after 2 to 5 minutes. The therapy with atropine and oximes is absolutely insufficient in case of a soman poisoning. The effectiveness of atropine and oximes can considerably be improved by a preliminary treatment with indirect parasympathomimetics, e.g., carbamic acid esters, such as pyridostigmine and physostigmine. Carbamic acid esters inhibit the acetylcholinesterase in a manner similar to that of phosphoric esters. However, the bond is of a shorter duration and completely reversible. The fact that the carbamates inhibit part of the acetylcholinesterase, if dosed suitably, and thus remove it from the reach of the phosphoric esters and phosphonates having a stronger and prolonged inhibition may well be a decisive factor for their protective action, provided that the pretreatment started in time.
Also, the treatment of a poisoning caused by organophosphorus insecticides requires prompt medical care in any case. Since medical care in case of harvesters cannot always be accomplished promptly, there is a need for drugs prophylactically counteracting an intoxication. The use of carbamic acid esters for this purpose has already been described (Leadbeater, L. Chem. in Brit. 24, 683, 1988). The same applies to the effectiveness of carbamic acid esters in the pretreatment of a soman poisoning in animal experiments (Fleischer, J. H., Harris, L. W. Biochem. Pharmacol. 14, 641, 1965, Berry, W. K., Davies, D. R. Biochem. Pharmacol, 19, 927, 1970). The effective dosage of drugs to be applied prophylactically must not impair reactivity and functional capacity. However, carbamic acid esters have a low therapeutic index. As compared to pyridostigmine, an increased protective action can be achieved by physostigmine, however, the side effects are more severe.
DE-OS 41 15 558 describes a prophylactic antidote consisting of a combination of pyridostigmine or physostigmine and N-methyl-4-piperidyl-1-phenylcyclopentane carboxylate-hydrochloride or arpenal, sycotrol, carmiphene or benactyzine, and, as an additional compelling component, a tranquilizer, i.e., diazepam or clonazepam. The undesired effects of physostigmine or pyridostigmine can therefore not be suppressed by the listed parasympatholytics alone, requiring the additional administration of tranquilizers which have side effects that are problematic.